Feasibility of Classification of Triple Negative Breast Cancer by Immunohistochemical Surrogate Markers

Kim, Sewha; Moon, Byung In; Lim, Woosung; Park, Sanghui; Cho, Min Sun; Sung, Sun Hee

doi:10.1016/j.clbc.2018.03.012

Cited by 49 publications

(51 citation statements)

References 21 publications

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“…One recent study established a surrogate IHC panel for the molecular classification of TNBC and examined the relationship between the IHC-based subtypes and patients' clinicopathological features [39]. However, in that study, the researchers did not perform gene expression profiling on the samples.…”

Section: Discussionmentioning

confidence: 99%

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

et al. 2020

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Background. Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and Methods. By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). Results. We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [−], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR−, CD8−, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR−, CD8−, FOXC1−, DCLK1 +), and (e) IHC-based unclassifiable (AR−, CD8−, FOXC1−, DCLK1 −). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion. We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.

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Section: Discussionmentioning

confidence: 99%

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

et al. 2020

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“…There are currently no routine diagnostic tools for identifying CL breast cancer in the clinic and gene expression profiling remains the gold standard for molecular subtyping of TNBC. 77 As such, CL breast cancer is often more broadly categorised as TNBC in the clinic and targeted therapies are non-existent for patients with CL breast cancer. 78 Efforts are already underway to better diagnose CL breast cancer in the clinic and it will be interesting to see the potential of fatty acid metabolism genes to serve as markers of CL breast cancer.…”

Section: Discussionmentioning

confidence: 99%

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

et al. 2020

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BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.

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“…Lehmann et al analyzed 587 TNBC cases and identified 6 TNBC subtypes displaying unique gene expression profile: two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL) and a Luminal Androgen Receptor subtype (LAR), composed of AR driven tumors, and that has been suggested to be correlated to the previously identified by Farmer et al “Molecular Apocrine” subtype (MA) (Farmer et al, 2005; Lehmann et al, 2011; Lehmann-Che et al, 2013). Among these subtypes, LAR type was found to be associated with older patient age, apocrine histologic features, low density of stromal tumor-infiltrating lymphocytes (TIL), and low Ki-67 labeling index (Kim et al, 2018). Sex steroid hormone receptors, ER and PGR, have always played a leading role in the development and progression of BC; however, in the last years, AR has emerged as a prominent player to focus attention on.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and Androgen Receptor: Emerging Players in Breast Cancer

Bandini

Fanini

2019

Front. Genet.

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Breast cancer (BC) is the most common cause of cancer among women, with a high incidence rate occurrence every year worldwide despite advances in its management. BC is characterized by a spectrum of subtypes which respond differently to treatments due to their biological features, representing the main issue in the control of this type of malignancy. Androgen receptor (AR) is emerging as a target to investigate among hormone receptors, since it seems to play a role at various stages of development of specific BC subsets. For this reason, in recent years AR has become very important in the clinical practice, although its role remains controversial. A number of studies have proposed a correlation between microRNAs (miRNAs), a class of gene expression modulators, and AR in prostate cancer (PC), but there are still few evidences about the relationship between miRNAs and AR in BC. The purpose of this review is to present a state of the art scenario with consideration to the most recent discoveries about miRNAs involved in the AR associated pathogenesis of BC, in order to provide new insights into the role of miRNAs as key drivers in the modulation of AR, and possible actors in the development and progression of BC. Moreover, we consider findings about involvement of AR signaling in all stages of BC, highlighting its association with different subsets of breast carcinomas and with pre- and postmenopausal state of patients.

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Feasibility of Classification of Triple Negative Breast Cancer by Immunohistochemical Surrogate Markers

Cited by 49 publications

References 21 publications

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance

MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer

MicroRNAs and Androgen Receptor: Emerging Players in Breast Cancer

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